: Obesity is a health problem of enormous proportions with few effective therapeutic treatments. The regulation of body weight and body adiposity occurs through coordinated actions of peripheral and central mechanisms, which control food intake and energy expenditure. Leptin is secreted from adipocytes and functions as a peripheral signal of lipid stores to the brain. There are gender difference in percent body fat as well as in the distribution of body fat, and we have determined there are gender differences in sensitivity to centrally administered leptin. The present experiments are proposed to determine if gonadal hormones, specifically estrogen, effects the expression and sensitivity of the critical signaling variant of the leptin receptor (Ob-Rb). The first series of experiments will investigate if there are gender differences in distribution and expression of the Ob-Rb using in situ hybridization real-time PCR and Western blot analysis. In the second set of experiments, we will investigate if there are differences in the activation of intracellular proteins activated as part of the leptin receptor-signaling cascade, STAT3 and SOCS-3, by utilizing Western Blot analysis and Ribonuclease Protection Assays. Lastly, we will assess whether the gonadal hormone estrogen, affects Ob-Rb expression and activation, by comparing gonadectomized animals with and without hormone replacement and measuring Ob-Rb distribution, expression, and activation.